Oral spirochetes, including Treponema denticola, comprise about 40 percent of the bacteria in periodontal pockets and are linked to the progression and severity of periodontal disease. Despite their obvious relevance to periodontal disease, they are vastly understudied. Oral spirochetes are usually found in close association with the gingival epithelium, but our understanding of how T. denticola and other oral spirochetes establish themselves at this interface is limited. T. denticola and other oral spirochetes likely have evolved strategies to avoid host immune defenses, specifically the defenses initiated by the epithelial cell. The proposed studies will focus on the interactions of spirochetes with gingival epithelial cells and the modulation of molecules produced by these cells in response to bacterial challenge. Our studies to date demonstrate that T. denticola is resistant to a-defensins, and the susceptibility of other oral treponemes to beta-defensins will be examined (Aim 1). To define the mechanisms used by T. denticola to resist beta-defensins killing, we will explore strategies used by other bacteria to resist antimicrobial peptides, including bacterial proteases, binding of defensin to cell surfaces, and efflux pumps (Aim 2). The ability of T. denticola and other oral treponemes to induce production of beta-defensins will be examined in Aim 3. Our preliminary data suggest that T. denticola inhibits the induction of inflammatory cytokines by other bacterial products, similar to the "chemokine paralysis" that has been described for Porphyromonas gingivalis LPS. We will examine the modulation of cytokines and adhesion molecules from epithelial cells stimulated by T. denticola (Aim 4), with the goal of identifying the signaling pathways that are affected by the spirochetes. Lastly, we will determine the components of T. denticola (Aim 5) that induce production of a-defensins and antagonize the induction of inflammatory cytokines. This study will further our understanding of the pathogenesis of periodontal disease by providing a more complete understanding of how T. denticola and other oral spirochetes evade the innate immune response.